Methods and apparatus to stimulate heart atria

ABSTRACT

A method and apparatus for treatment of hypertension and heart failure by increasing vagal tone and secretion of endogenous atrial hormones by excitory pacing of the heart atria. Atrial pacing is done during the ventricular refractory period resulting in atrial contraction against closed AV valves, and atrial contraction rate that is higher than the ventricular contraction rate. Pacing results in the increased atrial wall stress. An implantable device is used to monitor ECG and pace the atria in a nonphysiologic manner.

This application claims the benefit of the U.S. Provisional PatentApplication 60/826,847, filed Sep. 25, 2006, the entirety of which isincorporated by reference herein.

BACKGROUND

The present invention generally relates to implantable devices forcardiac stimulation and pacing therapy, and more particularly, thepresent invention is concerned with cardiac therapies involving thecontrolled delivery of electrical stimulations to the heart for thetreatment of hypertension, congestive heart failure, and an apparatusfor delivering such therapies with the objective of altering sympatheticand parasympathetic nerve stimulation and secretion of hormones by theheart muscle and to cause vasodilatation of blood vessels.

Congestive Heart Failure

Congestive heart failure (CHF) occurs when muscle cells in the heart dieor no longer function properly, causing the heart to lose its ability topump enough blood through the body. Heart failure usually developsgradually, over many years, as the heart becomes less and lessefficient. It can be mild, scarcely affecting an individual's life, orsevere, making even simple activities difficult.

Congestive heart failure (CHF) accounts for over 1 million hospitaladmissions yearly in the United States (U.S.) and is associated with a5-year mortality rate of 40%-50%. In the U.S., CHF is currently the mostcostly cardiovascular disease, with the total estimated direct andindirect costs approaching $56 billion in 1999.

Recent advances in the treatment of CHF with medications, includingangiotensin-converting enzyme (ACE) inhibitors, beta-blockers(Carvedilol, Bisoprolol, Metoprolol), Hydralazine with nitrates, andSpironolactone have resulted in significantly improved survival rates.Although many medications have been clinically beneficial, they fallshort of clinician's expectations and as a result consideration hasturned to procedures and devices as additional and more potent heartfailure therapy.

There has been recent enthusiasm for biventricular pacing (pacing bothpumping chambers of the heart) in congestive heart failure patients. Itis estimated that 30% to 50% of patients with CHF have inter-ventricularconduction defects. These conduction abnormalities lead to adiscoordinated contraction of the left and right ventricles of analready failing and inefficient heart. When the right ventricle alone ispaced with a pacemaker, the delayed activation of the left ventricle,can also lead to significant dyssynchrony (delay) in left ventricularcontraction and relaxation.

Because ventricular arrhythmias continue to threaten CHF patients andmany anti-arrhythmic drugs have unacceptable side effects, asophisticated implantable cardioverter-defibrillator (ICD) device hasshown encouraging results. Biventricular pacing in combination with ICDsdemonstrates a trend toward improved survival. Preliminary data inanimals and humans using subthreshold (of the type that does not byitself cause heart muscle to contract) stimulation of the heart muscleto modulate cardiac contractility are encouraging and may furtherenhance the quality of life of CHF patients.

It is also clear that many patients with CHF are not candidates forbiventricular pacing or do not respond to this treatment strategy. Thisalso applies to other recent advances and experimental therapies. Thereis a clear need for new, better therapies that will improve and prolonglife of heart failure patients and reduce the burden on the medicalsystem. It is particularly important that these new therapies should notrequire a major surgery, prolonged stay in the hospital or frequentvisits to the doctor's office.

Hypertension

It is generally accepted that high blood pressure (HBP, also calledhypertension) is bad, but most people don't know why, and what the termreally means. In fact, all humans have high blood pressure some of thetime, and we wouldn't be able to function if we didn't (such as duringexercise). High blood pressure is only of concern when it persists forlong periods of time or is extremely high over a very short (hours)period of time. Its adverse effects usually take many years to develop.Clinically important HBP is very common. According to officialgovernment figures, it affects 50 million people in the United States.

While everyone has high blood pressure some of the time, many peoplelive their entire lives with moderately high blood pressure and neverknow it until it is notice on a routine visit to the doctor.Unfortunately, not all people are so lucky. In these people, high bloodpressure significantly increases the risk of a number of serious events,mainly strokes and heart attacks.

More specifically, the damage caused by high blood pressure is of threegeneral sorts. The first is the one everyone thinks of—bursting a bloodvessel. While this is dramatic and disastrous when it happens, it'sactually the least common of the three problems. It occurs mostfrequently in the blood vessels of the brain, where the smaller arteriesmay develop a weak spot, called an aneurysm. This is an area where thewall is thinner than normal and a bulge develops. When there is a suddensurge of pressure the aneurysm may burst, resulting in bleeding into thetissues. If this occurs in the brain, it is called a stroke. Incontrast, if this happens to the aorta (the main blood vessel in thebody), it is called a ruptured aortic aneurysm. Both of these events canlead to permanent damage and death.

The second adverse consequence of high blood pressure is that itaccelerates the deposition of cholesterol in the arteries forming ablockage. This problem, too, takes many years to develop, and it is verydifficult to detect until it causes a major blockage. The most importantsites to be affected are the heart, where the blockage can cause anginaand heart attacks; the brain, where it causes strokes; the kidneys,where it causes renal failure (and can also make the blood pressure goeven higher); and the legs, where it causes a condition known asintermittent claudication, which means pain during walking and may evenlead to losing a limb.

Third, high blood pressure puts a strain on the heart: Because it has towork harder than normal to pump blood against a higher pressure, theheart muscle enlarges, just as any other muscle does when it is usedexcessively. Over a long period of time, the high blood pressure canlead to congestive heart failure, the most frequent cause forhospitalization in the United States. Whatever the underlying cause,when the blood pressure reaches a certain level for a sufficient lengthof time it sets off a vicious cycle of damage to the heart, brain, andkidneys, resulting in further elevation of the pressure.

Classification of hypertension by its severity is somewhat arbitrarybecause there's no precise level of pressure above which it suddenlybecomes dangerous. Historically, blood pressure has been primarilyclassified according to the height of the diastolic pressure. Someonewhose diastolic pressure runs between 90 and 95 mm Hg may be regarded ashaving borderline hypertension, and when it's between 95 and 110 mm Hg,it's considered moderate, and at any higher levels, it's termed severe.Recent data suggests that the systolic pressure is as, and maybe moreimportant than, diastolic blood pressure in determining the patient'srisk for serious adverse events. Systolic hypertension is mainly seen inpeople over the age of 65 and is characterized by a high systolic, butnormal diastolic, pressure (a reading of 170/80 mm Hg would be typical).It's caused by an age-related loss of elasticity of the major arteries.Another form of HBP, Labile hypertension, is a commonly used term fordescribing people whose pressure is unusually labile or variable. Themost dangerous type of HBP is called malignant hypertension or highblood pressure with evidence on physical exam that this pressure causingan acute deleterious affecting on vital organ function. Malignanthypertension is regarded as an emergency requiring immediate treatmentin a hospital. Not surprisingly, if untreated, malignant hypertensioncan be rapidly fatal. Although more people are treated with drugsnowadays than before, malignant hypertension is still common.

The objective of treatment is not simply to lower the blood pressure,but to prevent its consequences, such as strokes and heart attacks.According to the American Heart Association high blood pressure ispresent in 50,000,000 Americans (Defined as systolic pressure 140 mm Hgor greater, and/or diastolic pressure 90 mm Hg or greater, or takingantihypertensive medication). Of those with HBP, 31.6 percent areunaware they have it; 27.4 percent are on medication and have itcontrolled; 26.2 percent are on medication but don't have their HBPunder control; and 14.8 percent aren't on medication. In most cases,high blood pressure can be controlled with one or a combination of oraldrugs. Of those patients that take medication to control HBP, manysuffer from debilitating side effects of these drugs such as heartarrhythmias, inability to exercise or do normal activities of dailyliving and impotence.

Electric Activity of The Heart

In a given cardiac cycle (corresponding to one “beat” of the heart), thetwo atria contract, forcing the blood therein into the ventricles. Ashort time later, the two ventricles contract, forcing the blood thereinto the lungs (from the right ventricle) or through the body (from theleft ventricle). Meanwhile, blood from the body refills the right atriumand blood from the lungs refills the left atrium, waiting for the nextcycle to begin. A healthy adult human heart may beat at a rate of 60-80beats per minute (bpm) while at rest, and may increase its rate to140-180 bpm when the adult is engaging in strenuous physical exercise,or undergoing other physiologic stress.

The healthy heart controls its rhythm from its sinoatrial (SA) node,located in the upper portion of the right atrium. The SA node generatesan electrical impulse at a rate commonly referred to as the “sinus” or“intrinsic” rate. This impulse is delivered from the SA node to theatrial tissue when the atria are intended to contract. The electricalsignal continues to propagate from the atrial tissue through theatrioventricular (AV) node, a specialized collection of tissue thatserves as a “gatekeeper” for the impulses traveling between the atriaand the ventricles. After a suitable delay (on the order of 140-220milliseconds), the signal finally propagates to the ventricular tissueand the ventricles are stimulated to contract. SA node is the naturalpacemaker of the heart. If it is disabled, there are other specializedareas of the heart muscle that can generate an intrinsic heart rate.

The ventricular muscle tissue is much more massive than the atrialmuscle tissue. The atrial muscle tissue need only produce a contractionsufficient to move the blood a very short distance from the respectiveatrium to its corresponding ventricle. The ventricular muscle tissue, onthe other hand, must produce a contraction sufficient to push the bloodthrough the complete circulatory system of the entire body. Even thoughtotal loss of atrial contraction can lead to a small reduction ofcardiac output it is not an immediate risk to life. Conversely, theatria of the heart can sustain a higher number of contractions perminute than the ventricles without endangering life.

Electronic Cardiac Pacemakers

It is the function of a electronic pacemaker (pacemaker) to provideelectrical stimulation pulses to the appropriate chamber(s) of the heart(atrium, ventricle, or both) in the event the heart is unable to beat onits own (i.e., in the event either the SA node fails to generate its ownnatural stimulation pulses at an appropriate sinus rate, or in the eventsuch natural stimulation pulses do not effectively propagate to theappropriate cardiac tissue). Most modern pacemakers accomplish thisfunction by operating in a “demand” mode where stimulation pulses fromthe pacemaker are provided to the heart only when it is not beating onits own, as sensed by monitoring the appropriate chamber of the heartfor the occurrence of a P-wave or an R-wave. If a P-wave or an R-wave isnot sensed by the pacemaker within a prescribed period of time (whichperiod of time is often referred to as the “escape interval”), then astimulation pulse is generated at the conclusion of this prescribedperiod of time and delivered to the appropriate heart chamber via apacemaker lead. Pacemaker leads are isolated wires equipped with sensingand stimulating electrodes.

Modern programmable pacemakers are generally of two types: (1)single-chamber pacemakers, and (2) dual-chamber pacemakers. In asingle-chamber pacemaker, the pacemaker provides stimulation pulses to,and senses cardiac activity within, a single-chamber of the heart (e.g.,either the right ventricle or the right atrium). In a dual-chamberpacemaker, the pacemaker provides stimulation pulses to, and sensescardiac activity within, two chambers of the heart (e.g., both the rightatrium and the right ventricle). The left atrium and left ventricle canalso be paced, provided that suitable electrical contacts are madetherewith.

Much has been written and described about the various types ofpacemakers and the advantages and disadvantages of each. For example,U.S. Pat. Nos. 4,712,555 of Thornander et al. and 5,601,613 of Florio etal. present background information about pacemakers and the manner inwhich they interface with a patient's heart. These patents are herebyincorporated by reference in their entirety.

One of the most versatile programmable pacemakers available today is theDDDR pacemaker. This pacemaker represents a fully automatic pacemakerwhich is capable of sensing and pacing in both the atrium and theventricle, and is also capable of adjusting the pacing rate based on oneor more physiological factors, such as the patient's activity level. Itis commonly accepted that the DDDR pacemaker is superior in that it canmaintain AV synchrony while providing bradycardia (slow heart beat)support. It is also generally more expensive than other, simpler typesof pacemakers. A description of DDDR pacing is included in thisdiscloser as a state of the art.

In general, DDDR pacing has four functional states: (1) P-wave sensing,ventricular pacing (PV); (2) atrial pacing, ventricular pacing (AV); (3)P-wave sensing, R-wave sensing (PR); and (4) atrial pacing, R-wavesensing (AR).

It is accepted as important and advantageous, for the patient withcomplete or partial heart block, that the PV state of the DDDR pacemakertracks the atrial rate, which is set by the heart's SA node, and thenpaces in the ventricle at a rate that follows this atrial rate. It isassumed that because the rate set by the SA node represents the rate atwhich the heart should beat in order to meet the physiologic demands ofthe body (at least for a heart having a properly functioning SA node)the rate maintained in the ventricle by such a pacemaker is trulyphysiologic.

In some instances, a given patient may develop dangerously fast atrialrhythms, which result from a pathologic arrhythmia such as apathological tachycardia, fibrillation or flutter. In these cases, aDDDR pacemaker may pace the ventricle in response to the sensed atrialarrhythmia up to a programmed maximum tracking rate (MTR). The MTRdefines the upper limit for the ventricular rate when the pacemaker istracking the intrinsic atrial rate. As a result, the MTR sets the limitabove which the ventricles cannot be paced, regardless of the intrinsicatrial rate. Thus, the purpose of the MTR is to prevent rapidventricular stimulation, which could occur if the intrinsic atrial ratebecomes very high and the pacemaker attempts to track atrial activitywith 1:1 AV synchrony.

When the intrinsic atrial rate exceeds the MTR the pacemaker mayinitiate one or more upper atrial rate response functions—such asautomatically switching the pacemaker's mode of operation from an atrialtracking mode to a non-atrial rate tracking mode.

The heart's natural response to a very high atrial rate involves anatural phenomenon known as “blocking”—where the AV node attempts tomaintain a form of AV synchrony by “dropping out” occasional ventricularbeats when the high atrial rate exceeds a certain natural thresholdi.e., the refractory period of the heart tissue. The blocking phenomenonis often expressed as a ratio of the atrial beats to the ventricularbeats (e.g. 6:5, 4:3, etc.). Of particular importance is a 2:1 blockcondition where there are two atrial beats for every one ventricularbeat. The 2:1 block condition is a natural response to a very highatrial rate, during which full ventricular rate synchronization (i.e. ata 1:1 ratio) would be dangerous to the patient.

Some known pacemakers emulate this 2:1 condition, by tracking P-waves upto the device's programmed total refractory period (TARP) of the heart.That is, P-waves which fall in the total refractory period are nottracked, and the device is said to have a “2:1 response mode”. Duringthe 2:1 block response mode, the ventricles are paced at a lower ratethan the natural atrial rate, because P-waves occurring soon afterventricular events are ignored for the purposes of calculating theventricular pacing rate. As a result, the 2:1 block response modeprevents the pacemaker from pacing the ventricles at a tachycardia rate.

The 2:1 block response mode is an effective response for dealing withshort incidences of high atrial rates and in preventing occurrence of apacemaker mediated tachycardia resulting from retrograde P-waves.However, the 2:1 block response mode may become uncomfortable for thepatient if it is maintained for an extended period of time due toprogrammed long atrial refractory periods, because the pacing rate willbe ½ of the required physiologic rate.

Many more advanced pacemaker operation modes have been described andsometimes implemented. Some of these modes included sensing abnormallyhigh atrial rates and prevented them from causing rapid ventricularrates. Common to prior pacing no attempt has been made to induce a rapid(faster than normal) atrial rate by pacing or to pace atria at ratehigher than ventricles.

Pacemaker Syndrome

Although pacemakers provide relief from life-threatening arrhythmias andcan improve quality of life significantly, they also can function in anonphysiologic manner, which is accompanied by nontrivial morbidity.Pacemakers functioning in the VVI mode (e.g., a pacing mode in which ofthe native atrial electrical or contractile state are not sensed andignored by the pacemaker) have been noted to sacrifice the atrialcontribution to ventricular output. In some instances, and because ofthis lack of feedback, the timing of native atrial contraction andpacemaker-induced ventricular contraction is such that the atrialcontraction occurred during ventricular contraction or against closedatrio-ventricular (A-V) valves (Tricuspid and Mitral), producing reverseblood flow and nonphysiologic pressure waves. The A-V valves normallyopen passively whenever the pressure in the atrium exceeds the pressurein the ventricle. The pressure in the ventricles is low duringventricular diastole (or the normal termed vernticular filling period).In the case of non-physiological pacing, the A-V vales are not able tobe normally opened by the pressure in the atrium during atrialcontraction as the ventricles are in their pumping period (calledventricular systole) and the pressure in the ventricles significantlyexceeds the maximum possible pressure able to be generated in the atria.This abnormal, non-physiological relationship of atrial to ventricularcontraction can occur in other pacing modes if a patient's heart tissueis susceptible to allowing abnormal retrograde (e.g., from the ventricleto the atria) conduction of native or pacemaker-induced ventricularelectrical activity.

Pacemaker syndrome was first described as a collection of symptomsassociated with right ventricular pacing. Since its first discovery,there have been many definitions of pacemaker syndrome, and theunderstanding of the cause of pacemaker syndrome is still underinvestigation. In a general sense, pacemaker syndrome can be defined asthe symptoms associated with right ventricular pacing relieved with thereturn of A-V and V-V synchrony. Recently, most authors have recognizedthat pacemaker syndrome, which initially was described in patients withventricular pacemakers, is related to nonphysiologic timing of atrialand ventricular contractions, which may occur in a variety of pacingmodes. Some have proposed renaming the syndrome “A-V dyssynchronysyndrome,” which more specifically reflects the mechanism responsiblefor symptom production.

The symptoms of pacemaker syndrome included dyspnea (shortness ofbreath) and even syncope (fainting) Syncope is temporary loss ofconsciousness and posture, described as “fainting” or “passing out.”It's usually related to temporary insufficient blood flow to the brain.It's a common problem, accounting for 3 percent of emergency room visitsand 6 percent of hospital admissions. It most often occurs when 1) theblood pressure is too low (hypotension) and/or 2) the heart doesn't pumpa normal supply of blood to the brain.

In pacemaker syndrome patients, syncope occurs secondary to retrograde,ventricular to atrial (V-A) conduction resulting in the contraction ofthe atria against closed A-V valves. One effect of the elevated atrialand venous pressures associated with the contraction against closed A-Vvalves is to cause a vagal afferent response resulting in peripheralvasodilatation leading to a marked lowering of blood pressure (termedhypotension). Syncope is usually associated with systolic blood pressuredeclines of greater than 20 mm Hg that can occur with the onset ofpacing.

Pacemaker syndrome can also lead to decreased cardiac output, withresultant increase in left atrial pressure and left ventricular fillingpressure. Not only can this decrease in blood flow lead to syncope, thisincreases in atrial pressure or ventricular filling pressure can alsoresult in increased production of atrial natriuretic peptide (ANP) andB-type natriuretic peptide (BNP). ANP and BNP are potent arterial andvenous vasodilators that can override carotid and aortic baroreceptorreflexes attempting to compensate for decreased blood pressure. Patientswith pacemaker syndrome exhibit increased plasma levels of ANP, andpatients with so called atrial pressure “cannon a waves” (cause byatrial contraction against a closed valve) have higher plasma levels ofANP than those without “cannon a waves”.

Natriuretic Peptides (ANP and BNP)

Atrial natriuretic peptide (ANP) is a hormone that is released frommyocardial cells in the atria and in some cases the ventricles inresponse to volume expansion and increased wall stress. Brainnatriuretic peptide (BNP) is a natriuretic hormone that is similar toANP. It was initially identified in the brain but is also present in theheart, particularly the ventricles.

The release of both ANP and BNP is increased in heart failure (CHF), asventricular cells are recruited to secrete both ANP and BNP in responseto the high ventricular filling pressures. The plasma concentrations ofboth hormones are increased in patients with asymptomatic andsymptomatic left ventricular dysfunction, permitting their use indiagnosis. A Johnson and Johnson Company Scios sells popular intravenous(IV) medication Natrecor (nesiritide), a recombinant form of theendogenous human peptide for the treatment of decompensated CHF. Theadvent of Natrecor marked an important evolution in the understandingand treatment of acute heart failure.

Both ANP and BNP have diuretic, natriuretic, and hypotensive effects.They also inhibit the renin-angiotensin system, endothelin secretion,and systemic and renal sympathetic activity. Among patients with CHF,increased secretion of ANP and BNP may partially counteract the effectsof norepinephrine, endothelin, and angiotensin II, limiting the degreeof vasoconstriction and sodium retention. BNP may also protect againstcollagen accumulation and the pathologic remodeling that contributes toprogressive CHF.

SUMMARY

It has been observed that—while clearly deleterious to the majority ofheart disease patients—the phenomenon of the reduction of blood pressurein response to nonphysiologic pacing can be beneficial by reducing bloodpressure in the group of patients with severe hypertension andparticularly ones with malignant drug refractory hypertension thatfrequently results in strokes and sudden death.

The inventors have developed a pacemaker that is counterintuitively useddissynchronously to generate different atrial and ventricularcontraction rates. Specifically, a higher rate of atrial contractionsthan ventricular contractions is generated. It is understood that thismay result in suboptimal performance of the heart. However, theinventors propose that this disadvantage of lower blood pressure fromthe reflex vasodilation caused by nonphysiologic pacing canparadoxically benefit some heart failure patients if the increasedANP-BNP secretion from increased atrial pressures sufficiently increasesthe release of ANP and BNP hormones to a level that overcomes potentialdetriments from reduced atrial contribution to cardiac output.

One Embodiment AV Blocked Electric Stimulation of the Heart

One embodiment disclosed here uses a modified implanted electroniccardiac pacemaker to increase ANP and BNP secretion by pacing the rightatrium of the patient at an appropriately high rate. In the firstdescribed embodiment, patients have either a natural atrioventricularblock (AV block) or have an AV block induced by heart tissue ablation orsome other appropriate procedure. For example in patients with aso-called third-degree AV block (complete AV block, no AV conduction),no atrial impulses reach the ventricles, and ventricular rhythm ismaintained by a subsidiary natural pacemaker. Since subsidiarypacemakers must be below the level of block, their location is in partdetermined by the site of block. In third-degree AV nodal block, theventricular rhythm is usually maintained by pacemakers in the AVjunction with resultant narrow QRS complexes. In third-degree AV blocklocalized to the bundle branches, ventricular rhythm is maintained by apacemaker in the Purkinje fibers, with resultant wide QRS complexes. Thejunctional pacemaker rate is usually faster (40-80 beats/min) comparedwith the peripheral Purkinje network (20-40 beats/min). In suchpatients, a dual chamber pacemaker can be used to pace atria at a ratemuch higher than the ventricles without the risk of patient developingdangerous ventricular tachycardia (rapid heart beat) as the atrialimpulses, either native or pacemaker-induced, are not conducted to theventricle. An atrioventricular (AV) node ablation is a known medicalprocedure that destroys a part of the heart's normal electrical system.The combination of pacing and AV node ablation is sometimes usedclinically in patients with chronic atrial fibrillation and rapidventricular response that poorly respond to drug therapy.

This is accomplished by cauterizing the AV node, which is locatedbetween the upper heart chamber (atria) and the lower heart chambers(ventricles). Once the AV node is cauterized, none or few impulses fromthe atria will be able to reach the ventricles. Currently, an AV nodeablation is performed when the patient's rhythm disturbance (arrhythmia)originates in the atria and its effects on atrial or ventricularfunction cannot be controlled adequately with other measures. Apermanent pacemaker is installed afterwards, to keep the heart beatingat a normal rate. In this case, at least one pacemaker lead is connecteddirectly to a ventricle.

Another Embodiment Refractory Period Electric Stimulation of the Heart

Inventors realized that it is desired to implement nonphysiologic pacingwith the purpose of increasing atrial wall stress and cause vagal reflexand hormonal release without blocking natural AV conduction. Inventorsdiscovered that such pacing modality is possible utilizing naturallyoccurring periods in the electric cyclic activity of the heart when theheart muscle conduction is blocked by so called refractory periods.

In the heart are specialized tissue collections that have a uniqueproperty, they rhythmically emit electrical impulses. The cause of thesephenomena is the “leaky membrane” that allows the regular exchange ofSodium, Potassium, and Calcium ions and causes a change in thepolarization of the cells. Sodium ions move into the cell and start thedepolarization, Calcium ions extend that depolarization. When theCalcium ions stop entering the cell Potassium ions move in and therepolarization of the cell begins. To simplify this, the Sodium startsthe cells stimulation, the Calcium extends that stimulation to allow theentire muscle to contract before Potassium comes along and tells it torelax for a moment and get ready for the next wave. The most importantaspect of the repolarization—depolarization cycle of the individualheart muscle elements that is relevant to this invention is the“refractory” period where the cells reset for the next wave andtemporarily cannot be electrically stimulated to contract.

These atrial, AV and ventricular refractory periods have two stages, theAbsolute and Relative refractory periods. In the Absolute refractoryphase, the conduction system and heart muscle are in a “drained” stateand need a moment to “recharge” to be able to electrically and/ormechanically respond to another electrical stimulus. Thus, a pacemakerimpulse applied to these structure during this time would not beelectrically conducted or cause the heart muscle to contract. In therelative refractory period that follows the absolute refractory period,the electrical conducting tissues and/or heart muscle cells are notfully “recharged” but may conduct and/or contract if excited with astrong pacing signal.

Refractory period of the atrial in the naturally beating heart beginsand ends before the end of the absolute refractory period of theventricle. Therefore, it is possible to generate an electrical stimulusto pace the atria of the heart during the ventricular refractory periodand generate the atrial contraction but this electrical stimulus willnot propagate through the AV node to the ventricle and cause aventricular contraction.

To maximize the affect of the atrial contraction in the terms of maximumatrial muscle wall stress and the subsequent neural activation andhormonal release, it is desired to cause a contraction of the atriumwhen the atrium is filled with blood and its walls are distended. It isalso desired to cause atrial contraction against the closed AV valve,causing the phenomenon similar to the pacemaker syndrome. This maximumstress in the atrial wall caused by the atrial contraction can beexpected to result in the maximum vasodilatation of peripheral bloodvessels that will achieve the desired reduction of systemic arterialblood pressure.

The atria of the heart naturally contract during the approximately 100ms following the P-wave of the surface ECG of the heart. The Q-wave ofthe surface ECG corresponds to the beginning of the absolute refractoryperiod of the atria. The atria passively fill with blood during theventricular systole, which occurs following the Q-wave of the surfaceECG. Approximately half-way or 100-150 ms into the ventricular systoleperiod, the atria are fully expanded and primed with blood and thewindow of opportunity for the maximum benefit from nonphysiologic atrialpacing begins. The ventricles contracts during the ventricular systoleof the heart and are absolutely refractory to electric stimulationduring this period. Importantly, the atrial refractory period endsbefore the 50% of the ventricular systole has elapsed. The atria are nowelectrically and mechanically “armed” and can be triggered to contractby a pacing impulse. This window of opportunity can be defined asoccurring from the end of the atrial refractory period (approximately 30to 50% into the ventricular systole following the Q wave) and the end ofthe ventricular refractory period that corresponds to the middle of theT-wave, which is also the time when the aortic valve opens. During thistime window, it is possible to apply a pacing signal to the atrium ofthe heart, generate a nonphysiologic atrial contraction withoutprovoking the undesired nonphysiologic ventricular contraction. Thetiming diagram on the FIG. 5 of this application illustrates theprincipal of nonphysiologic atrial contraction.

In summary, inventors discovered that the following novel algorithmallows pacemaker stimulated atrial contraction in an intact naturallybeating heart:

A. The end of atrial refractory period is detected or predicted, basedon physiologic monitoring of the heart, for example by detectingsuitable event points of the patient's surface ECG or intracardiacelectrogram. The end of atrial refractory period also corresponds to theend of the depolarization and mechanical contractile activity of theatrial heart muscle.

B. The atrium is paced to contract following the end of the refractoryperiod of the atrium but before the end of the refractory period of theventricle, for example in the middle of ventricular systole.

C. In one proposed embodiment the resulting contraction of the atriumoccurs in the later part of the ventricular systole when atrium isdistended by passive filling with blood. A non-physiological, pacedatrium contraction is then caused during this period which causes theatrium to contract against the closed AV valve, increasing atrialpressure and wall stress leading to beneficial neural and hormonalstimuli. These stimuli are expected to result in 1) peripheralvasodilatation and reduction of blood pressure in hypertensive patientsor 2) increased ANP/BNP secretion leading to beneficial physiologicaland clinical sequelae in patients with CHF.

In one embodiment of the invention, a sensing and pacing lead of apacemaker (implantable or temporary) is placed in an atrium (such as RA)of the heart. The intracardiac ECG is sensed for signs of atrial andventricular depolarization and repolarization. The beginning and end ofthe atrial refractory period is predicted following a known delay afterthe P wave or R wave of the heart. For example, the atrium can be paced150 milliseconds (ms) after the detected R wave. The desired delay canbe recalculated by the embedded software based on the heart rate or setby the physician during the office visit of the patient. All modernpacemakers include suitable sensing, programmability and telemetryfunctions.

It is understood that there are many ways to detect various phases ofthe electric heart activity cycle using surface or intracardiac ECG,pressures, wall motion or heart sound sensors. It is imagined that someof these signals can be used to synchronize the proposed nonphysiologicpacing to the desired window of the heart cycle. Common to all of thispotential embodiments, the heart atrium (right or left or both) is pacedafter the end of the atrial refractory period and before the end of theventricular refractory period.

In this invention, a pacemaker is counter intuitively useddissynchronously to generate different atrial and ventricularcontraction rates. Specifically, a higher rate of atrial contractionsthan ventricular contractions is generated. It is understood that thismay result in suboptimal performance of the heart. The inventors proposethat this disadvantage will be offset by the benefit of the increasedbeneficial vasodilatory stimulus and hormonal secretion by the heartatria in hypertensive and heart failure patients.

Electronic pacemakers are currently used to replace or supplement thenatural pacing nodes of the heart by applying electric excitory signalsto the heart muscle to cause contraction and blood pumping cycle.Pacemakers are used in patients with diseased nodes (slow heart beat)and defective (blocked) conduction pathways. Bi-ventricular pacemakerspace both ventricles of the heart to restore synchrony between theventricles.

Generally, the conventional wisdom of all pacing therapies for the heartdisease is as follows. A human heart consists of four chambers—two atriaand two ventricles. In order for the heart to efficiently perform itsfunction as a pump, the atrial muscles and ventricular muscles shouldcontract in a proper sequence and in a timed relationship, as they do ina healthy heart. Therefore electronic pacemakers are used to restore thenormal heartbeat or to restore synchrony between different chambers ofthe heart. It is understood that the methods and embodiments describedin this patent may be incorporated into existing pacemaker devices, suchas the pacemakers, biventricular pacemakers or ICDs.

A method for treating hypertension by pacing a heart of a patient havingan atria and a ventricle has been developed, the method comprising:pacing at least one atrium of the heart, where the said atrial pacingoccurs after the end of the atrial refractory period, during theventricular refractory period of the heart and results in an atrialcontraction that is not immediately followed by a ventricularcontraction. The method may include paced atrial contraction occursagainst a closed AV valve of the heart. The method may further includesensing the ECG and detection of a P wave or an R wave followed a presetdelay and the excitory pacing pulse. In addition, the method may includepacing occurs between the R wave and before a middle of a T wave. Inaddition, the method where the pacing occurs approximately 100 to 200 msafter the R wave. Further, the method include pacing results in twoatrial contraction per each ventricular contraction of the heart, whereevery second atrial contraction in nonphysiologic and paced. The methodmay include atrial pacing occurs on every second heartbeat, or pacingoccurs approximately 250 to 350 ms after the P wave. The method mayfurther include paced atrial contraction occurs against a closed AVvalve of the heart in a middle of systole after substantial filling ofthe atria with blood.

SUMMARY OF THE DRAWINGS

A preferred embodiment and best mode of the invention is illustrated inthe attached drawings that are described as follows:

FIG. 1 illustrates the electric excitory pathways and chambers of ahuman heart.

FIG. 2 illustrates the embodiment of the invention with a two leadpacing system.

FIG. 3 illustrates one sequence of natural and induced stimulationpulses.

FIG. 4 illustrates intermittent asynchronous pacing.

FIG. 5 illustrates timing of the refractory period pacing.

DETAILED DESCRIPTION

FIG. 1 shows a normal heart. Electrical pulses in the heart arecontrolled by special groups of cells called nodes. The rhythm of theheart is normally determined by a pacemaker site called the sinoatrial(SA) node 107 located in the posterior wall of the right atrium 102 nearthe superior vena cava (SVC) 101. The SA node consists of specializedcells that undergo spontaneous generation of action potentials at a rateof 100-110 action potentials (“beats”) per minute. This intrinsic rhythmis strongly influenced by autonomic nerves, with the vagus nerve beingdominant over sympathetic influences at rest. This “vagal tone” bringsthe resting heart rate down to 60-80 beats/minute in a healthy person.Sinus rates below this range are termed sinus bradycardia and sinusrates above this range are termed sinus tachycardia.

The sinus rhythm normally controls both atrial and ventricular rhythm.Action potentials generated by the SA 107 node spread throughout theatria, depolarizing this tissue and causing right atrial 102 and leftatrial 106 contraction. The impulse then travels into the ventricles viathe atrioventricular node (AV node) 108. Specialized conduction pathwaysthat follow the ventricular septum 104 within the ventricles rapidlyconduct the wave of depolarization throughout the right 103 and left 105ventricles to elicit the ventricular contraction. Therefore, normalcardiac rhythm is controlled by the pacemaker activity of the SA nodeand the delay in the AV node. Abnormal cardiac rhythms may occur whenthe SA node fails to function normally, when other pacemaker sites(e.g., ectopic pacemakers) trigger depolarization, or when normalconduction pathways are not followed.

FIG. 2 shows a heart treated with one embodiment of the invention. Pulsegenerator (pacemaker) 201 is implanted in a tissue pocket in thepatient's chest under the skin. In this embodiment the generator 201 isconnected to the heart muscle by two electrode leads. The ventricularlead 202 is in contact with the excitable heart tissue of the rightventricle 103. The atrial lead 203 is in contact with the excitableheart tissue of the right atrium 102. It is understood that thepacemaker can have more leads such as a third lead to pace the leftventricle 105. It is expected that in future cardiac pacemakers willhave even more leads connecting them to various parts of the anatomy.

Leads 203 and 202 can combine sensing and pacing electrodes as known andcommon in the field. The atrial lead 203 can therefore sense the naturalintrinsic contractions of the atria before they occur and communicatethem to the generator 201. The generator is equipped with theprogrammable logic that enables it to sense signals, process theinformation, execute algorithms and send out electric signals to theleads.

In this embodiment the natural conduction path between the SA node 107and the AV node 108 is blocked. The patient may already have a naturalcomplete AV block. In this case no intervention is needed. If thepatient has functional electric pathways from atria to ventricles, thepatient's AV node can be disabled (blocked) by tissue ablation. It isunderstood that many irreversible and reversible methods of selectivelyblocking conduction in the heart are known. These include treatment withchemical agents and blocking with subthreshold electric stimulation(non-excitatory stimulation that does not cause muscle fibers tocontract). Ablation of the AV node is used as an example since it iswidely accepted and easily performed using RF energy catheters. Otherdevices that use cold, laser and ultrasound energy to perform ablationare also known.

FIG. 3 illustrates one possible embodiment of the invention with asequence of stimulation pulses. Pulses are simplified and presented asrectangular blocks spaced in time as represented by the X-axis.

Trace 301 illustrates the natural or intrinsic rate generated by the SAnode of the heart. The SA node generates pulses 304, 305, 306 and 307.These pulses can be sensed by the atrial lead 203.

In response to the sensing of intrinsic atrial pulses, the pulsegenerator 201 generates a series of pulses represented by the trace 302.Pulses are conducted to the atria by the atrial lead 203. Devicegenerated atrial stimulation pulses 311, 313, 315 and 317 are insynchrony with the SA node pulses 304, 305, 306 and 307. They representthe intrinsic heart rate. The generator 201 (based on an embeddedalgorithm) also generates extra atrial pulses 312, 314 and 316. Togethersynchronous pulses 311, 313, 315, 317 and asynchronous pulses 312, 314,316 determine the atrial rate of the heart.

Trace 303 represents ventricular stimulation pulses 321, 322, 323 and324 conducted to the ventricle of the heart by the ventricular lead 202.The AV node of the heart in this embodiment is blocked. Therefore theventricular stimulation is generated by the generator 201 based on anembedded algorithm. To ensure better performance of the heartventricular pulses 321, 322, 323 and 324 are synchronized to thesynchronous atrial pulses 311, 313, 315 and 317 with a short delay 308determined by the embedded algorithm that simulates the natural delay ofthe AV node conduction.

The algorithm illustrated by the FIG. 3 can be described as a followingsequence:

a. sensing an intrinsic SA node pulse (P-wave),

b. generating a synchronous atrial pacing pulse,

c. calculating the intrinsic atrial rate based on previous SA node pulseintervals,

d. generating synchronous ventricular pacing signal delayed from thesynchronous atrial pacing signal at the ventricular rate equal to theintrinsic SA node excitation rate (sinus rhythm),

d. calculating the desired increased atrial rate, such as for example, a2:1 (A:V) rate,

e. generating asynchronous atrial pacing signal based on the calculatedincreased atrial rate, and

f. waiting for the next intrinsic SA node pulse (P-wave).

It is understood that this example of an algorithm is an illustrationand many other embodiments of the invention can be proposed. It can beenvisioned that more than 2:1 (atrial:ventricular) rate can be toleratedby the patient or that less than 2:1 rate is desired such asaccelerating every second atrial beat.

It may be not essential to preserve the natural sinus rhythm (from theSA node) is preserved. In some patients it may be desired for thealgorithm to take over the heart rate and force all the atrialcontraction. Pacing modalities that do not rely on the SA node togenerate the heart rate are known and used to treat bradycardia. The SAnode of a patient can be ablated similar to the AV node and the embeddedpacemaker algorithm will pace the atria. Alternatively, atria may bepaced if the natural SA node pulse is not senses within the expectedtime from the last ventricular contraction. Various activity sensorssuch as accelerometers can be used to accelerate the heart rate asneeded.

FIG. 4 illustrates intermittent application of the proposed therapy. Itis possible that some patients will not need or will not be able totolerate continuous asynchronous A-V (atria-ventricular) pacing. In suchpatient period of normal (synchronous) pacing 401 is followed by theperiod of asynchronous (accelerated atrial) pacing 402 followed again bythe period of synchronous pacing 403. The ventricular pacing rate 405 inthis example stays the same. Switching between rates can be based ontiming, patient's activity or physiologic feedbacks. For example, thepattern of therapy using electrical stimuli to generate high atrialrates can be intermittent of varying duration of accelerated atrialpacing in intervals of 10-60 minute durations occurring, for example, 3times per day.

Commonly, in comparison to previous devices, this embodiment of theinvention purposefully creates ratios of atrial to ventricularcontraction higher than 1:1, such as for example in the range of 1:1 to4:1. In addition, any previous device that allowed more that a 1:1 ratioof contraction based this relationship on sensing native atrialdepolarization and deferring generation of a ventricular pacing stimulus(skipping premature ventricular beats). In contrast, in the illustratedembodiment, the higher than 1:1 rate is intentionally and controllablyinitiated by the implantable generator. As a result the atrial rate isincreased to a rate which causes the release of sufficient endogenousnaturetic hormone to result in a therapeutically beneficial increase inblood plasma levels of the hormones or increased levels in any othervascular or non-vascular space in which these hormones a found.

It is desirable to cause a therapeutic increase of blood plasma ANP andBNP via an increased endogenous release of ANP and BNP from the atria ofthe patient's heart. Atrial release is mediated via increase of atrialwall stress. The best embodiment of the invention known to the inventorsat the time of the invention is rapid pacing of the atria that isexpected to increase the rate of contractions of the atria and releaseANP and BNP. The invention has been described in connection with thebest mode now known to the applicant inventors. The invention is not tobe limited to the disclosed embodiment. Rather, the invention covers allof various modifications and equivalent arrangements included within thespirit and scope of the appended claims.

FIG. 5 illustrates the refractory period atrial pacing of the heart. Theheart (See FIG. 1) has intact electric conduction includingsubstantially normal physiologic intact A-V node conduction delay.Pacing in this embodiment is implemented by electric stimulation with anatrial lead 203 (See FIG. 2). Sensing of electric activity can beperformed with the atrial lead 203 or ventricular lead 202.

Natural pacemaker or SA node of the heart initiates the Heart cycle withthe P wave 501 of the ECG that corresponds to the beginning of atrialcontraction. It is also the beginning of the heart systole. Atrialpressure 502 increases and atrial volume 503 decreases. This timecorresponds to the beginning of the atrial refractory period 508. Duringthis period atria can not be paced to contract.

The P wave of the ECG is followed by the Q wave 505 that signifies thebeginning of the isovolumic contraction of the ventricle. Ventricularpressure 504 rise begins rapidly. In response the Tricuspid and Mitralvalves of the heart close. Ventricular refractory period 510 begins. Atthe end of isovolumic contraction 509 Pulmonary and Aortic valves openand the ejection of blood from the ventricle begins. Ventricularpressure reaches its peak in the middle of systole 519. Atrium ispassively filled with blood as it relaxes 513. Approximately by themiddle of systole both heart atria are filled with blood 511 and theirrefractory period is over. Atria are primed for a new contraction whilethe ventricle is ejecting blood. A-V valves are closed. At the same timethe ventricle is still refractory and will not start another contractionin response to a natural or artificial pacing stimulus. Heart waves Q505, R 506 and S 507 are commonly used markers of the beginning of theisovolumic contraction and the beginning of ventricular ejection (Swave). All modern pacemakers are equipped with meant to read and analyzethe ECG that are suitable for this embodiment of the invention.

Systole ends when the aortic valve closes 512. Isovolumic relaxation ofthe ventricle starts. This point also corresponds to the middle of the Twave 514 of the ECG. Importantly for the invention, the middle of T wave514 corresponds to the end of the absolute refractory period of theventricle. At the end of the T-wave Tricuspid and Mitral valves open andthe atrium volume starts to drop 520 as the blood starts to flow fromthe atria into ventricles to prime them for the next ventricularcontraction and ejection.

For this embodiment of the invention the window of pacing opportunity515 starts after the end of the atrial refractory period 508 andpreferably but not exclusively after the atrium is filled with blood 511and extended. During this window the atrium is primed and can be pacedwith a pacemaker pulse 516 that can occur at approximately the middle ofsystole or approximately 100-150 ms following the detected R wave 506and/or 300 ms after P wave 501 is detected. Both P-wave and R-wave canbe used by themselves or in combination to trigger pacing 516. Inresponse to pacing 516 atrium contracts generating a pressure rise 517that results in the desired increased stress of the atrial wall muscle,release of atrial hormones and vagal neuro activation. Significantly thewindow 515 overlaps the ventricular refractory period 510. Pacing atriaoutside of that time period is not desired since it can cause anarrhythmia and a premature ventricular beat.

As a result of the proposed therapy heart atria will beat at the rate2:1 in relation to the heart ventricles. First physiologic atrialcontraction 502 will be initiated by the natural pacemaker of the heart.Second non-physiologic atrial contraction 517 will occur during theheart systole, when the ventricle is refractory to stimulation. It maynot be necessary to pace during every natural heart beat. Pacing can beapplied only during part of the day or very second or third beat to giveheart the needed rest and prevent of delay potential chronic dilation ofthe double-paced atria and potential heart failure.

FIG. 6 Further illustrates relationship between the electric activity ofthe heart and the proposed novel pacing method. Atrial refractory periodcorresponds to the depolarization of cells in the atrium muscle 601.Ventricular refractory period corresponds to the depolarization of cellsin the muscle of the ventricle 510. Pacing 516 generates second atrialcontraction during the window 515. Appropriate trigger points such asP-Q-R-S waves of the ECG 603 can be used by the embedded pacemakersoftware to generate the pacing spike 516 after an appropriate delay haselapsed from the selected P or R wave or both. This delay can beadjusted by the physician by reprogramming the pacemaker orautomatically corrected based on the patient's heart rate. In mostgeneral terms pacing should occur after the R wave and before the T waveof the ECG 603. A delay of approximately 100-150 ms can be implementedafter the R wave to allow atria to safely exit the relative refractoryperiod and to allow atria to distend and fill with blood.

The invention has been described in connection with the best mode nowknown to the applicant inventors. The invention is not to be limited tothe disclosed embodiment. Rather, the invention covers all of variousmodifications and equivalent arrangements included within the spirit andscope of the appended claims.

1. A method for pacing a heart of a patient suffering from hypertension or sodium retention, the method comprising: artificially pacing an atrium of the heart during a period between an end of an atrial refractory period and an end of a ventricular refractory period, wherein the artificial pacing includes delivery of excitatory stimulation to the atrium; wherein the excitatory stimulation causes the atrium to contract while a heart valve associated with the atrium is closed such that the contraction distends the atrium, and the distending atrium results in a therapeutic effect of a reduction in at least one of vasoconstriction and sodium retention.
 2. The method in claim 1 wherein muscles in the atrium are distended by the contraction of the atrium.
 3. The method in claim 1, wherein the artificial pacing is applied to multiple atria of the heart.
 4. The method in claim 1, wherein the distention causes the atrium to releases natriuretic peptides which result in the therapeutic effect.
 5. The method in claim 1, wherein the artificial pacing is performed solely during the period between the end of the atrial period and the end of the ventricular refractory period.
 6. A method in claim 1, where the artificial pacing stimulates contraction of the atrium without an immediately following contraction of a ventricle of the heart.
 7. The method in claim 1, where the contraction of the atrium against the closed heart valve distends atrial walls of the atrium.
 8. The method in claim 1 further comprising detecting a P wave of the heart.
 9. A method as in claim 1, further comprising detection of a T wave of the heart.
 10. A method as in claim 1, where the artificial pacing occurs during an absolute refractory phase of a ventricular refectory period.
 11. A method for stressing walls of an atrium of a heart of a mammalian patient comprising: detecting an end of an atrial refractory period of the heart, predicting an end of a ventricular refractory period of the heart, artificially pacing the atrium of the heart during a period between the detected end of the atrial refractory period and the predicted end of the ventricular refractory period, wherein the artificial pacing causes the atrium of the heart to contract while a trio-ventricular valve of the atrium is closed such that the contraction distends the walls of the atrium, and the distention of the walls results in a therapeutic effect of a reduction in at least one of vasoconstriction and sodium retention.
 12. The method in claim 11, wherein the artificially pacing the heart results in a rate of contractions of the atrium which is faster than a rate of ventricular contractions.
 13. The method in claim 11, wherein the artificial pacing results in an artificially induced contraction of the atrium which is succeeded by a naturally occurring contraction of the atrium.
 14. The method in claim 13, wherein the artificial pacing is applied to cyclically apply the artificially induced contraction of the atrium and the naturally occurring contraction of the atrium.
 15. The method in claim 11, wherein the artificially pacing includes four successive atrial contractions pacing applied to yield two successive contractions of the atrium which are followed by two successive of the naturally occurring contractions of the atrium. 